Tivorbex

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and
nonselective NSAIDs of up to three years duration have shown an increased risk
of serious cardiovascular (CV) thrombotic events, myocardial infarction (MI),
and stroke, which can be fatal. All NSAIDs, both COX-2 selective and
nonselective, may have a similar risk. Patients with known CV disease or risk
factors for CV disease may be at greater risk. To minimize the potential risk
for an adverse CV event in patients treated with an NSAID, use the lowest
effective dose for the shortest duration possible. Physicians and patients should
remain alert for the development of such events, even in the absence of
previous CV symptoms. Inform patients about the signs and/or symptoms of
serious CV events and the steps to take if they occur.

Two large, controlled, clinical trials of a COX-2 selective
NSAID for the treatment of pain in the first 10-14 days following CABG surgery
found an increased incidence of MI and stroke [see CONTRAINDICATIONS].

There is no consistent evidence that concurrent use of
aspirin mitigates the increased risk of serious CV thrombotic events associated
with NSAID use. The concurrent use of aspirin and an NSAID, such as
indomethacin, does increase the risk of serious gastrointestinal (GI) events [see
Gastrointestinal (GI) Effects].

NSAIDs, including TIVORBEX, can cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the esophagus, stomach, small intestine, or
large intestine, which can be fatal. These serious adverse events can occur at
any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients, who develop a serious upper GI adverse event on
NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months,
and in about 2%-4% of patients treated for one year. These trends continue with
longer duration of use, increasing the likelihood of developing a serious GI
event at some time during the course of therapy. However, even short-term NSAID
therapy is not without risk.

In patients taking indomethacin, intestinal ulceration
has been associated with stenosis and obstruction. Gastrointestinal bleeding
without obvious ulcer formation and perforation of pre-existing sigmoid lesions
(diverticulum, carcinoma, etc.) have occurred. Increased abdominal pain in
ulcerative colitis patients or the development of ulcerative colitis and
regional ileitis have been reported to occur.

Prescribe NSAIDs, including TIVORBEX, with extreme
caution in patients with a prior history of ulcer disease or GI bleeding.
Patients with a prior history of peptic ulcer disease and/or GI bleeding who
use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that
increase the risk for GI bleeding in patients treated with NSAIDs include
longer duration of NSAID therapy, concomitant use of oral corticosteroids or
anticoagulants, smoking, use of alcohol, older age, and poor general health
status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and therefore, special care should be taken in treating
this population.

To minimize the potential risk for an adverse GI event in
patients treated with an NSAID, use the lowest effective dose for the shortest
possible duration. Patients and physicians should remain alert for signs and
symptoms of GI ulceration and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI adverse event is
suspected. This should include discontinuation of the NSAID until a serious GI
adverse event is ruled out. For high risk patients, alternative therapies that
do not include NSAIDs should be considered.

Hepatic Effects

Borderline elevations of one or more liver tests may
occur in up to 15% of patients taking NSAIDs, including TIVORBEX. These
laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately
three or more times the upper limit of normal) have been reported in
approximately 1% of patients in clinical trials with NSAIDs. In addition, rare
cases of severe hepatic reactions, including jaundice and fatal fulminant
hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes
have been reported.

A patient with symptoms and/or signs suggesting liver
dysfunction, or in whom abnormal liver test values have occurred, should be
evaluated for evidence of the development of a more severe hepatic reaction
while on therapy with indomethacin. If clinical signs and symptoms consistent
with liver disease develop, or if systemic manifestations occur (e.g.,
eosinophilia, rash, etc.), discontinue TIVORBEX immediately.

Hypertension

NSAIDs, including TIVORBEX, can lead to new onset or
worsening of pre-existing hypertension, either of which may contribute to the
increased incidence of CV events.

Use NSAIDs, including TIVORBEX, with caution in patients
with hypertension. Monitor blood pressure (BP) closely during the initiation of
NSAID treatment and throughout the course of therapy.

Congestive Heart Failure And Edema

Fluid retention and edema have been observed in some
patients taking NSAIDs. Use TIVORBEX with caution in patients with fluid
retention or heart failure.

In a study of patients with severe heart failure and
hyponatremia, indomethacin was associated with significant deterioration of
circulatory hemodynamics, presumably due to inhibition of prostaglandin
dependent compensatory mechanisms.

Renal Effects

Use caution when initiating treatment with TIVORBEX in
patients with considerable dehydration.

Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury. Renal toxicity has also been seen in
patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of a
nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate over renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver
dysfunction, those taking diuretics and ACE inhibitors, patients with volume
depletion, and the elderly. Discontinuation of NSAID therapy is usually
followed by recovery to the pretreatment state [see DRUG INTERACTIONS].

Increases in serum potassium concentration, including
hyperkalemia, have been reported with use of indomethacin, even in some
patients without renal impairment. In patients with normal renal function,
these effects have been attributed to a hyporeninemichypoaldosteronism state.

Advanced Renal Disease

No information is available from controlled clinical
studies regarding the use of indomethacin in patients with advanced renal
disease. Therefore, treatment with TIVORBEX is not recommended in patients with
advanced renal disease. If TIVORBEX therapy must be initiated, monitor patient
renal function closely.

Anaphylactic Reactions

As with other NSAIDs, anaphylactic reactions may occur in
patients without known prior exposure to TIVORBEX. TIVORBEX is contraindicated
in patients with the aspirin triad. This symptom complex typically occurs in
asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other
NSAIDs [see CONTRAINDICATIONS].

Seek emergency help in cases where an anaphylactic
reaction occurs.

Central Nervous System Effects

TIVORBEX may aggravate depression or other psychiatric
disturbances, epilepsy, and parkinsonism, and should be used with considerable
caution in patients with these conditions. Discontinue TIVORBEX if severe CNS
adverse reactions develop.

TIVORBEX may cause drowsiness; therefore, caution
patients about engaging in activities requiring mental alertness and motor
coordination, such as driving a car. Indomethacin may also cause headache.
Headache which persists despite dosage reduction requires cessation of therapy
with TIVORBEX.

Skin Reactions

NSAIDs, including TIVORBEX, can cause serious skin
adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome
(SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious
events may occur without warning. Patients should be informed about the signs
and symptoms of serious skin manifestations, and discontinue the use of
TIVORBEX at the first appearance of skin rash or any other sign of
hypersensitivity [see CONTRAINDICATIONS].

Fetal Toxicity

Starting at 30 weeks gestation, TIVORBEX and other NSAIDs
should be avoided by pregnant women as premature closure of the ductus
arteriosus in the fetus may occur. If this drug is used during this time period
in pregnancy, the patient should be apprised of the potential hazard to a fetus
[see Use in Specific Populations].

Corticosteroid Treatment

TIVORBEX cannot be expected to substitute for
corticosteroids or to treat corticosteroid insufficiency. Abrupt
discontinuation of corticosteroids may lead to exacerbation of
corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy
should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.

Masking Of Inflammation And Fever

The pharmacological activity of TIVORBEX in reducing
inflammation, and possibly fever, may diminish the utility of diagnostic signs
in detecting infectious complications of presumed noninfectious, painful
conditions.

Hematological Effects

Anemia may occur in patients receiving NSAIDs, including
TIVORBEX. This may be due to fluid retention, occult or gross GI blood loss, or
an incompletely described effect upon erythropoiesis. In patients receiving
long-term therapy with NSAIDs, including TIVORBEX, check hemoglobin or
hematocrit if they exhibit any signs or symptoms of anemia or blood loss. TIVORBEX
is not indicated for long-term treatment.

NSAIDs inhibit platelet aggregation and have been shown
to prolong bleeding time in some patients. Unlike aspirin, their effect on
platelet function is quantitatively less, of shorter duration, and reversible.
Carefully monitor patients treated with TIVORBEX who may be adversely affected
by alterations in platelet function, such as those with coagulation disorders
or patients receiving anticoagulants.

Use In Patients With Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma.
The use of aspirin in patients with aspirin-sensitive asthma has been
associated with severe bronchospasm which can be fatal. Since cross reactivity,
including bronchospasm, between aspirin and other NSAIDs has been reported in
such aspirin-sensitive patients, TIVORBEX is contraindicated in patients with
this form of aspirin sensitivity and should be used with caution in all
patients with preexisting asthma [see CONTRAINDICATIONS].

Monitoring

Because serious GI tract ulcerations and bleeding can
occur without warning symptoms, physicians should monitor for signs or symptoms
of GI bleeding. For patients on long-term treatment with NSAIDs, periodically
check their CBC and chemistry profile including liver function tests.
Discontinue TIVORBEX if clinical signs and symptoms consistent with liver or
renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen. TIVORBEX is not indicated
for long-term treatment.

Ocular Effects

Corneal deposits and retinal disturbances, including
those of the macula, have been observed in some patients who had received
prolonged therapy with TIVORBEX. Be alert to the possible association between
the changes noted and TIVORBEX. It is advisable to discontinue therapy if such
changes are observed. Blurred vision may be a significant symptom and warrants
a thorough ophthalmological examination. Since these changes may be asymptomatic,
ophthalmologic examination at periodic intervals is desirable in patients
receiving prolonged therapy. TIVORBEX is not indicated for long-term treatment.

Patient Counseling Information

See FDA-approved patient
labeling (Medication Guide). Patients should be informed of the following
information before initiating therapy with an NSAID and periodically during the
course of ongoing therapy. Patients should also be encouraged to read the NSAID
Medication Guide that accompanies each prescription dispensed.

Cardiovascular Effects

NSAIDs, including TIVORBEX, may
cause serious CV side effects, such as myocardial infarction or stroke, which
may result in hospitalization and even death. Although serious CV events
can occur without warning symptoms, advise patients to be alert for the signs
and symptoms of chest pain, shortness of breath, weakness, slurring of speech,
and to ask for medical advice when observing any indicative sign or symptoms.
Inform patients of the importance of this follow-up [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Effects

NSAIDs, including TIVORBEX, can cause GI discomfort and,
rarely, serious GI side effects, such as ulcers and bleeding, which may result
in hospitalization and even death. Although serious GI tract ulcerations and
bleeding can occur without warning symptoms, advise patients to be alert for
the signs and symptoms of ulcerations and bleeding, and to ask for medical
advice when observing any indicative sign or symptoms including epigastric
pain, dyspepsia, melena, and hematemesis. Inform patients of the importance of
this follow-up [see WARNINGS AND PRECAUTIONS].

Adverse Skin Reactions

NSAIDs, like TIVORBEX, can cause serious skin side
effects such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and
toxic epidermal necrolysis (TEN), which may result in hospitalizations and even
death. Although serious skin reactions may occur without warning, advise
patients to be alert for the signs and symptoms of skin rash and blisters,
fever, or other signs of hypersensitivity such as itching, and to ask for
medical advice when observing any indicative signs or symptoms. Advise patients
to stop the drug immediately if they develop any type of rash and contact their
physicians as soon as possible [see WARNINGS AND PRECAUTIONS].

Weight Gain And Edema

Advise patients to promptly report to their physicians
signs or symptoms of unexplained weight gain or edema during treatment with
TIVORBEX [see WARNINGS AND PRECAUTIONS].

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction
(e.g., difficulty breathing, swelling of the face or throat). Instruct patients
to seek immediate emergency help if these occur [see WARNINGS AND PRECAUTIONS].

Fetal Toxicity

Inform pregnant women to avoid use of TIVORBEX and other
NSAIDs starting at 30 weeks gestation, [see WARNINGS AND PRECAUTIONS and
Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment Of Fertility

Carcinogenesis

In an 81-week chronic oral toxicity study in the rat at
doses up to 1 mg/kg/day (0.08 times the MRHD on a mg/m² basis),
indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or
hyperplastic changes related to treatment in carcinogenic studies in the rat
(dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at
doses up to 1.5 mg/kg/day (0.06 times [mice] and 0.12 times [rats] the MRHD on
a mg/m² basis, respectively).

Mutagenesis

Indomethacin did not have any mutagenic effect in in
vitro bacterial tests and a series of in vivo tests including the host-mediated
assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in
mice.

Impairment of Fertility

Indomethacin at dosage levels up to 0.5 mg/kg/day had no
effect on fertility in mice in a two generation reproduction study (0.02 times
the MRHD on a mg/m² basis) or a two litter reproduction study in
rats (0.04 times the MRHD on a mg/m² basis).

Use In Specific Populations

Pregnancy

Risk Summary

There are no adequate and well-controlled studies of
TIVORBEX in pregnant women. Starting at 30 weeks gestation, TIVORBEX, and other
NSAIDs, should be avoided by pregnant women as premature closure of the ductus
arteriosus in the fetus may occur. TIVORBEX can cause fetal harm when
administered starting at 30 weeks gestation. If the drug is used during this
time period in pregnancy, the patient should be apprised of the potential
hazard to the fetus. Prior to 30 weeks gestation, TIVORBEX should be used
during pregnancy only if the potential benefit justifies the potential risk to
the fetus. In animal reproduction studies, retarded fetal ossification was
observed with administration of indomethacin to mice and rats during
organogenesis at doses 0.16 and 0.32 times, respectively, the maximum
recommended human dose (MRHD, 120 mg).

Clinical Considerations

Fetal and Neonatal Adverse Reactions

The known effects of indomethacin and other NSAIDs on the
human fetus during the third trimester of pregnancy include: constriction of
the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension;
non-closure of the ductus arteriosus postnatally which may be resistant to
medical management; myocardial degenerative changes, platelet dysfunction with
resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal
injury/dysgenesis which may result in prolonged or permanent renal failure,
oligohydramnios, gastrointestinal bleeding or perforation, and increased risk
of necrotizing enterocolitis.

Labor or Delivery

The effects of TIVORBEX on labor and delivery in pregnant
women are unknown. In rat studies, maternal exposure to NSAIDs, as with other
drugs known to inhibit prostaglandin synthesis, increased the incidence of
dystocia, delayed parturition, and decreased pup survival.

Data

Animal data

Reproductive studies were conducted in mice and rats at
dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal
ossification at 4 mg/kg/day (0.16 times [mice] and 0.32 times [rats] the MRHD
on a mg/m² basis, respectively) considered secondary to the
decreased average fetal weights, no increase in fetal malformations was
observed as compared with control groups. Other studies in mice reported in the
literature using higher doses (5 to 15 mg/kg/day, 0.20 to 0.60 times MRHD on a
mg/m² basis) have described maternal toxicity and death, increased
fetal resorptions, and fetal malformations. Comparable studies in rodents using
high doses of aspirin have shown similar maternal and fetal effects.

Maternal indomethacin administration of 4.0 mg/kg/day
during the last 3 days of gestation was associated with an increased incidence
of neuronal necrosis in the diencephalon in the live-born fetuses however no
increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the
control groups. Administration of 0.5 or 4.0 mg/kg/day to offspring during the
first 3 days of life did not cause an increase in neuronal necrosis at either
dose level.

Nursing Mothers

Based on available published data, indomethacin may be
present in human milk. In one study, levels of indomethacin in breast milk were
below the sensitivity of the assay ( < 20 mcg/L) in 11 of 15 women using doses
ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily)
in the postpartum period. Based on these levels, the average concentration
present in breast milk was estimated to be 0.27% of the maternal
weight-adjusted dose. In another study indomethacin levels were measured in
breast milk of eight postpartum women using doses of 75 mg daily and the
results were used to calculate an estimated infant daily dose. The estimated
infant dose of indomethacin from breast milk was less than 30 μg/day or
4.5 μg/ kg/day assuming breast milk intake of 150 ml/kg/day. This is 0.5%
of the maternal weight-adjusted dosage or about 3% of the neonatal dose for
treatment of patent ductus arteriosus. The developmental and health benefits of
human milk feeding should be considered along with the mother's clinical need
for TIVORBEX and any potential adverse effects on the human milk-fed child from
the drug or from the underlying maternal condition. Exercise caution when
TIVORBEX is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of TIVORBEX in pediatric patients
17 years of age and younger has not been established.

Geriatric Use

As with any NSAIDs, caution should be exercised in
treating the elderly (65 years and older) since advancing age appears to
increase the possibility of adverse reactions. Elderly patients seem to
tolerate ulceration or bleeding less well than other individuals and many
spontaneous reports of fatal GI events are in this population [see WARNINGS
AND PRECAUTIONS].

Indomethacin may cause confusion or rarely, psychosis [see
ADVERSE REACTIONS]; physicians should remain alert to the possibility of
such adverse effects in the elderly.

This drug is known to be substantially excreted by the
kidney and the risk of toxic reactions to this drug may be greater in patients
with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection and it may be
useful to monitor renal function [see WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 3/5/2014
This monograph has been modified to include the generic and brand name in many instances.